CHF2819: Pharmacological Profile of a Novel Acetylcholinesterase Inhibitor

Abstract

CHF2819 is a novel orally active acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD). CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this enzyme than against butyrylcholinesterase (BuChE). Moreover, CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE. In vivo CHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose-dependent manner increased acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine-induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) levels and increased extracellular levels of 5-hydroxytryptamine (5-HT) in the hippocampus, without modifying norepinephrine (NE) levels. By oral administration to young adult rats CHF2819 did not affect extracellular hippocampal levels of glutamate (Glu), aspartate (Asp), ã-aminobutyric acid (GABA), taurine (Tau), arginine (Arg) or citrulline (Cit).Functional observational battery (FOB) screening demonstrated that CHF2819 (1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic, neuromuscular, and sensorimotor domains, as well as physiological endpoints (body weight and temperature). CHF2819 induced, however, involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner.The neurochemical and behavioral profiles of CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer-type dementia as-53

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease

“…CHF2819 (Figure 40), an ovel geneserined erivative, shows AChE inhibition and produces central cholinergics timulation after oral administrationi nr ats. [116] CHF2819 significantly enhances AChE levels in the hippocampi of both young-adult and aged rats, considerably attenuates scopolamine-induced amnesia, and increases extracellularc oncentrations of hippocampal 5-hydroxytryptamine (5-HT), suggesting CHF2819c ould be of clinical interest mainly for the symptomatic treatment of AD patients. [117] In 2006, Rodríguez-Franco andc o-workersr eported as eries of tacrine-melatoninh ybrids( Figure41) as dual inhibitors of hAChEt hat showo xygen radical absorbance capacity (ORAC).…”

Structural Determinants ofTorpedocalifornicaAcetylcholinesterase Inhibition by the Novel and Orally Active Carbamate Based Anti-Alzheimer Drug Ganstigmine (CHF-2819)

“…[14][15][16][17] In particular, the pre-clinical profile of the 1) was evaluated, and this compound showed potential for the treatment of AD. [18][19][20][21][22][23][24] The results of first clinical trials evaluating the safety, tolerability, and pharmacodynamics of ganstigmine in AD patients are now available. 25 Furthermore, intraperitoneal and oral administration of ganstigmine was shown to rescue the neurodegenerative phenotype in AD11 anti-nerve growth factor mice, a transgenic model for AD.…”

Cholinesterase Inhibitors and Beyond

“…Among them, are the already mentioned phenserine [87] and gangstigmine [88], the selective BuChE inhibitor, cymserine [49], as well as new donepezil and galantamine derivatives [86]. Whether these compounds will demonstrate new actions beyond ChE inhibition remains to be determined.…”